Protozoan Parasites and Type I IFNs

Silva‐Barrios, Sasha; Stäger, Simona

doi:10.3389/fimmu.2017.00014

Cited by 46 publications

(53 citation statements)

References 111 publications

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“…However, we found here that type I IFNs and ISGs are up-regulated via cGAS/STING in vitro and in vivo. The importance of type I IFNs in controlling T. gondii infection is still controversial (49,50). Barik and co-workers (51) showed that induction of ISGs by IRF3 promotes replication of T. gondii when they infected mice with a tachyzoite of type I T. gondii (RH strain).…”

Section: Discussionmentioning

confidence: 99%

The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING

Wang

Zhao

et al. 2019

Journal of Biological Chemistry

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Toxoplasma gondii is an important neurotropic pathogen that establishes latent infections in humans that can cause toxoplasmosis in immunocompromised individuals. It replicates inside host cells and has developed several strategies to manipulate host immune responses. However, the cytoplasmic pathogen-sensing pathway that detects T. gondii is not well-characterized. Here, we found that cyclic GMP-AMP synthase (cGAS), a sensor of foreign dsDNA, is required for activation of anti-T. gondii immune signaling in a mouse model. We also found that mice deficient in STING (Sting gt/gt mice) are much more susceptible to T. gondii infection than WT mice. Of note, the induction of inflammatory cytokines, type I IFNs, and interferon-stimulated genes in the spleen from Sting gt/gt mice was significantly impaired. Sting gt/gt mice exhibited more severe symptoms than cGAS-deficient mice after T. gondii infection. Interestingly, we found that the dense granule protein GRA15 from T. gondii is secreted into the host cell cytoplasm and then localizes to the endoplasmic reticulum, mediated by the second transmembrane motif in GRA15, which is essential for activating STING and innate immune responses. Mechanistically, GRA15 promoted STING polyubiquitination at Lys-337 and STING oligomerization in a TRAF protein-dependent manner. Accordingly, GRA15-deficient T. gondii failed to elicit robust innate immune responses compared with WT T. gondii. Consequently , GRA15 ؊/؊ T. gondii was more virulent and caused higher mortality of WT mice but not Sting gt/gt mice upon infection. Together, T. gondii infection triggers cGAS/STING signaling, which is enhanced by GRA15 in a STING-and TRAF-dependent manner. The protozoan parasite Toxoplasma gondii can infect nearly all warm-blooded animals (1, 2). As for humans, nearly 30% of the world's population is infected with T. gondii (3). In healthy adults, T. gondii is controlled by the immune system and remains dormant in the brain. However, in immunocompromised individuals, a defect of the immune system leads to the reactivation of the T. gondii parasites and the development of toxoplasmosis. Reactivated parasite replication causes life-threatening brain damage with brain abscesses and necrotic areas (4). Thus, HIV/AIDS patients, cancer patients, and organ transplant recipients are highly susceptible to T. gondii infection. The infection of T. gondii parasites is recognized by pattern recognition receptors (PRRs). 4 Previous studies showed that TLR11 is the PRR of T. gondii in murine cells. TLR11 is able to detect the actin-binding protein Profilin, which is required for entry of T. gondii during infection. TLR11 and TLR12 form a heterodimer in murine dendritic cells (DC) after sensing Profilin and activate adaptor protein MyD88 to initiate downstream signaling for defense against T. gondii (5). Moreover, TLR7 and TLR9 are able to compensate for the loss of TLR11 by activating

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Section: Discussionmentioning

confidence: 99%

The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING

Wang

Zhao

et al. 2019

Journal of Biological Chemistry

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“…IFN-γ is a pro-inflammatory cytokine secreted primarily by T and natural killer (NK) cells, playing the role of an inducer of adaptive immune responses against protozoan infections [ 43 ]. We noticed that IFN-γ was blocked at 8 dpi and 16 dpi in all study groups regardless of the immune status of the host.…”

Section: Discussionmentioning

confidence: 99%

Changes in the immune system in experimental acanthamoebiasis in immunocompetent and immunosuppressed hosts

et al. 2018

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BackgroundAcanthamoebiasis is most often found in patients with immune deficiency, with infections facilitated by the intake of immunosuppressive drugs. The host immune response to Acanthamoeba spp. infection is poorly understood. Thus, in this study, we aimed to examine the course of Acanthamoeba spp. infection taking into account the host’s immunological status, including assessment of the hematological parameters, cytokine analysis, immunophenotypic changes in spleen populations, and histological spleen changes, which could help clarify some aspects of the immune response to acanthamoebiasis. In our experimental study, we used Acanthamoeba strain AM 22 isolated from the bronchoaspirate of a patient with acute myeloid leukaemia (AML) and atypical pneumonia symptoms.ResultsAcanthamoeba spp. affected the hematological parameters in immunocompetent and immunosuppressed mice and induced a change in spleen weight during infection. Moreover, analysis of anti-inflammatory (IL-4 and IL-10) and pro-inflammatory (IL-17A and IFN-γ) cytokines produced by splenocytes stimulated with concanavalin A demonstrated that Acanthamoeba spp. induced a selective Th1, Th2 and Th17 response at later stages of the infection in immunocompetent hosts. In the case of hosts with low immunity, Acanthamoeba elicited robust Th1 cell-mediated immunity without the participation of Th17. We observed suppression of CD8+ and CD4+ T lymphocytes and CD3+CD4-CD8- double-negative (DN) T lymphocyte populations in the beginning, and in the case of CD3+/CD4+/CD8+ double-positive (DP) T cells in the final phase of Acanthamoeba spp. infection in hosts with low immunity. Also, CD4+T lymphocytes and CD3+/CD4+ and CD3+/CD8+ lymphocyte counts during each stage of acanthamoebiasis were shown to be upregulated.ConclusionsWe demonstrated that analysis of the immune response and pathogenesis mechanisms of clinical isolates of Acanthamoeba spp. in an animal model not only has purely cognitive significance but above all, may help in the development of effective methods of pharmacological therapy especially in patients with low immunity.

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“…Previous studies have shown that IFN-β inhibits the Th1 immune response during protozoan parasitic infections [42][43][44][45]. We thus investigated whether the IFNAR signaling could be responsible for development of the Th1 subset present in target organs of VL.…”

Section: The Absence Of Ifnar Contributes To Th1 Inflammation and Parmentioning

confidence: 99%

TLR4 abrogates the Th1 immune response through IRF1 and IFN-β to prevent immunopathology during L. infantum infection

et al. 2020

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A striking feature of human visceral leishmaniasis (VL) is chronic inflammation in the spleen and liver, and VL patients present increased production levels of multiple inflammatory mediators, which contribute to tissue damage and disease severity. Here, we combined an experimental model with the transcriptional profile of human VL to demonstrate that the TLR4-IFN-β pathway regulates the chronic inflammatory process and is associated with the asymptomatic form of the disease. Tlr4-deficient mice harbored fewer parasites in their spleen and liver than wild-type mice. TLR4 deficiency enhanced the Th1 immune response against the parasite, which was correlated with an increased activation of dendritic cells (DCs). Gene expression analyses demonstrated that IRF1 and IFN-β were expressed downstream of TLR4 after infection. Accordingly, IRF1-and IFNAR-deficient mice harbored fewer parasites in the target organs than wild-type mice due to having an increased Th1 immune response. However, the absence of TLR4 or IFNAR increased the serum transaminase levels in infected mice, indicating the presence of liver damage in these animals. In addition, IFN-β limits IFN-γ production by acting directly on Th1 cells. Using RNA sequencing analysis of human samples, we demonstrated that the transcriptional signature for the TLR4 and type I IFN (IFN-I) pathways was positively modulated in asymptomatic subjects compared with VL patients and thus provide direct evidence demonstrating that the TLR4-IFN-I pathway is related to the nondevelopment of the disease. In conclusion, our results demonstrate that the TLR4-IRF1 pathway culminates in IFN-β production as a mechanism

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Protozoan Parasites and Type I IFNs

Cited by 46 publications

References 111 publications

The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING

The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING

Changes in the immune system in experimental acanthamoebiasis in immunocompetent and immunosuppressed hosts

TLR4 abrogates the Th1 immune response through IRF1 and IFN-β to prevent immunopathology during L. infantum infection

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